Intracellular activity of a membrane-active glycopeptide antibiotic against meticillin-resistant Staphylococcus aureus infection

Abstract

Staphylococcus aureus is a facultative intracellular pathogen and there are limited options for the treatment of severe intracellular bacterial infections. The membrane-active glycopeptide antibiotic Van-QC(8) is a permanent positively charged lipophilic vancomycin analogue that demonstrates high activity against clinically relevant drug-resistant Gram-positive bacteria both in vitro and in vivo. In this study, the intracellular activity of Van-QC(8) was evaluated against meticillin-resistant S. aureus (MRSA) infection in RAW macrophages. Furthermore, the mechanism of intracellular uptake of Van-QC(8) was investigated. Van-QC(8) showed time-and concentration-dependent bactericidal activity against intracellular MRSA. Van-QC(8) displayed significantly higher intracellular activity compared with vancomycin and linezolid. Cellular uptake of Van-QC(8) was found to be through clathrin-dependent and independent and caveolin-dependent and -independent endocytic pathways. The findings of this study suggest that Van-QC(8) could be translated clinically for the treatment of intracellular infections due to MRSA. (C) 2016 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.